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COVER STORY
New Horizons
in Glaucoma
Drug Delivery
Many products are in research and development, but there are numerous challenges.
BY GARY D. NOVACK, P h D
T
hirty years ago, John Shell, PhD, wrote a classic
article on drug delivery in which he defined the
problem of eye drops: this delivery method is
pulsatile, drugs have limited bioavailiablity due
to the many barriers through which they must pass
to reach the site of action, and the residence time of
the drug on the ocular surface is short-lived.1 The very
phrase ophthalmic drug delivery implies a challenge in
delivering medication to the eye. Eye drops are relatively inefficient delivery systems: they use volumes
(25-50 µL) larger than the available space (approximately 7 µL in the lower cul-de-sac),2 with relatively
poor bioavailability into the target site of the anterior
chamber (approximately 1%-5%). Eye drops also require
reliable administration, yet in one study, only about
20% to 30% of experienced glaucoma patients were
able to instill one drop in their eye without touching
the tip of the bottle against the ocular surface.3
Most people are able to take oral medication, and
there are numerous drug delivery systems for sustained
release (eg, transdermal). Some drugs can be administered by systemic routes (eg, antimetabolites for uveitis).
Unfortunately, the relative safety (also known as the
therapeutic index) of systemic therapy for purely ocular
disease is not optimal. Local therapy with minimal systemic exposure is therefore needed to achieve an acceptable therapeutic index.
I summarized many of the drug development and
regulatory challenges with a 21st century view of ophthalmic drug delivery systems approximately 5 years
42 GLAUCOMA TODAY JULY/AUGUST 2014
Figure 1. The Ocusert in place in the lower cul-de-sac of a
patient’s right eye.
ago.4 I wrote on glaucoma-specific delivery systems for
Glaucoma Today at approximately the same time.5 This
article provides an update on drug delivery systems for
glaucoma therapies.
I will use the analogy of purchasing airline tickets.
A generation ago, most tickets were bought through
travel agents. Today, most travelers connect to the airlines’ websites and personally make their reservations
and purchase their tickets. This puts the action in the
best place (ie, in the hands of the traveler who knows
his or her needs and preferences best). In the same way,
rather than have patients be responsible for their glaucoma pharmacotherapy, there is a movement to put
the responsibility in the hands of the ophthalmologist.
COVER STORY
(Courtesy of Avard L. Walker III.)
timolol maleate gel-forming solution [Timoptic-XE;
Valeant Pharmaceuticals]).14 To my knowledge, there
are no approved products using systems that are “in
the hands of the doctor” such as the Ocusert.
Figure 2. Dr. Novack and a friend backpacking in the Sierras
as an example of the “payload” issue.
SOURCES
There are relatively few full articles on ophthalmic
drug delivery systems currently in clinical evaluation.
Thus, for the purpose of this article, I have used a variety
of publicly available sources, including not only full articles but also abstracts from scientific meetings, published
patent applications and patents, clinical trial registries,
and press releases.
APPROACHES
Approved
Since the 19th century, pilocarpine has been known
as an effective ocular hypotensive agent, but its utility
is limited by muscarinic agonist adverse events (miosis
and accommodative spasm) and the drug’s short duration of action, requiring frequent instillation by the
patient.6 The Ocusert (Alza), inserted into the lower
cul-de-sac, released pilocarpine over approximately
7 days and was approved in the United States in the
early 1970s (Figure 1).7,8 Unfortunately, untoward
events such as “dose-dumping” and occlusion of the
visual axis limited its therapeutic value.9
US-marketed ocular hypotensive agents are administered by several means. A molecular, prodrug
approach was used for dipivefrin (Propine [Allergan],
a prodrug of epinephrine),10 levobunolol (Betagan
[Allergan], itself active as well as having an active
metabolite, dihydrolevobunolol),11 and latanoprost
(Xalatan [Pfizer], a prodrug of the active latanoprost
free acid).12 Other approaches in patients’ hands
include eye drops with a longer presumed residence
time and, therefore, longer presumed duration of
action (pilocarpine [Adsorbocarpine; Alcon]13 and
Investigational
Several investigational products are in the hands
of patients. These include lyophilization of latanoprost on Teflon strips,15 clonidine on plastic rods,16,17
hydrophilic contact lenses (NCT00445874; Vistakon
Pharmaceuticals),18 and a cationic emulsion of latanoprost (Catioprost; Novagali Pharma).19
As to investigational products in the hands of doctors, Mati Therapeutics has inserted latanoprost into
a punctal plug (NCT02014142). Ocular Therapeutix
has inserted travoprost into an erodible insert that is
placed in the punctum (NCT01845038). Both of these
devices are in phase 2 trials. A sub-Tenon injection of
anecortave acetate has been investigated.20 Peregrine
Ophthalmic is developing a liposomal latanoprost for
subconjunctival injection; the drug lowered mean IOP
from 28 to 15 mm Hg in an open-label study of six
patients.21 Allergan is evaluating an erodible, anterior
chamber implant of bimatoprost (EudraCT 2011005091-42). BioLight Israeli Life Sciences Investments
is evaluating a nonerodible, controlled-release insert
containing latanoprost for subconjunctival injection
(NCT02129673). Envisia Therapeutics is developing an
erodible implant of travoprost intended for intracameral placement. Replenish is developing an ophthalmic
“micropump” that is placed subconjunctivally and
that might have applications for glaucoma therapy.
Another bioerodible, sustained-release implant of
latanoprost intended for the subconjunctival space
is being developed by pSivida. ForSight Vision5 has
completed enrollment of a study of the “Helios” insert
(NCT01943721).
Ocular iontophoretic technology might be applicable to glaucoma (Aciont, EyeGate Pharma, ReAble
Empi [formerly Iomed], and Buckeye Pharmaceuticals),
as might an erodible intracameral implant from Icon
Biosciences.
With respect to the posterior segment, no drug is
approved for neuroprotection in glaucoma. Intraocular
drug delivery systems are approved for other indications. In the United States, these include nonerodible
intravitreal systems (ganciclovir [Vitrasert; Bausch +
Lomb] and fluocinolone acetonide [Retisert; Bausch +
Lomb]) and, in Europe, fluocinolone acetonide (Iluvien;
Alimera Sciences). Also approved in the United States
is an erodible intravitreal implant of dexamethasone
(Ozurdex; Allergan).
JULY/AUGUST 2014 GLAUCOMA TODAY 43
COVER STORY
“It will most likely be several years
until a novel drug delivery system is
available to patients with
glaucoma.”
CHALLENGES
In the decades since the approval of Ocusert, to my
knowledge, no ocular hypotensive insert or implant
has been approved. Why are advances in this area so
difficult? One challenge is akin to my difficulties when
backpacking (Figure 2). One day of food, even dehydrated, weighs about 750 g. My basic backpacking gear
weighs about 18 kg. I can carry approximately 27 kg
at most, so I can only transport about 12 days’ worth
of food before resupplying. In addition, all of my food
has to be stable at ambient temperatures (0ºC‑40ºC).
This “payload” issue is common to all ophthalmic drug
delivery systems, and it tends to limit options to potent
drugs and several months of therapy.
Drug solubility is also key in designing systems; only
some systems can work with macromolecules such
as antibodies. Another challenge is linking the nature
of the timed release of the molecule to the desired
therapeutic effect. There is a natural assumption that
zero-order is the Holy Grail. That is true for pilocarpine
and probably for timolol, but prostaglandin analogues
may be different in that more frequent instillation may
result in lower efficacy.22 For the treatment of acute
infection or inflammation, it may be desirable to have a
higher delivery rate early on followed by a lower maintenance level.23
The least risky approach to developing a novel drug
delivery product is to select a molecule that is already
approved and has an expiring patent. This strategy
assumes that the marketplace will recognize the
improvement, however, and will compensate for the
incremental cost of the new medication over a generic.
A higher-risk but higher-reward approach is to select
novel medications, especially those for which a delivery
system is the only way in which they could be used.
CONCLUSION
It will most likely be several years until a novel drug
delivery system is available to patients with glaucoma.
I encourage ophthalmologists and their staff members
to observe patients using eye drops to check for proper instillation.3 A host of educational materials is available from the American Academy of Ophthalmology
44 GLAUCOMA TODAY JULY/AUGUST 2014
and online. I also encourage clinicians to convey to
health care payers that patients’ adherence and performance are major issues in therapeutics and to emphasize that enhancements in this area are of clinical and
financial value. Finally, I encourage physicians to be
investigators for ongoing and upcoming clinical trials
of novel therapies. n
Portions of this article were presented during the
Innovator’s Symposium at the American Society of
Cataract and Refractive Surgery’s annual meeting on April
26, 2014, in Boston.
Gary D. Novack, PhD, is the president of
PharmaLogic Development in San Rafael,
California. He consults for numerous pharmaceutical and medical device firms but owns no
stock or proprietary interest. Dr. Novack may be
reached at (415) 472-2181; [email protected].
1. Shell JW. Ophthalmic drug delivery systems. Surv Ophthalmol. 1984;29:117-1128.
2. Mishima S, Gasset A, Klyce SD, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol Vis Sci.
1966;5:264-276.
3. Stone JL, Robin AL, Novack GD, et al. An objective evaluation of eye-drop instillation in glaucoma patients. Arch
Ophthalmol. 2009;127:732-736.
4. Novack GD. Ophthalmic drug delivery: development and regulatory considerations. Clin Pharmacol Ther.
2009;85:539-543.
5. Novack GD. Drug delivery systems in ophthalmology. Glaucoma Today. July/August 2009;7(5):31-33.
http://bmctoday.net/glaucomatoday/pdfs/GT0709_07.pdf. Accessed June 30, 2014.
6. Drance SM, Nash PA. The dose response of human intraocular pressure to pilocarpine. Can J Ophthalmol.
1971;6:9-13.
7. Armaly MF, Rao KR. The effect of pilocarpine Ocusert with different release rates on ocular pressure. Invest
Ophthalmol. 1973;12:491-496.
8. Shell JW. Ocular therapy by controlled drug delivery: The Ocusert System. Ophthalmic Surg Lasers. 1974;5:73-77.
9. Pearson DC. Complications with the use of Ocusert [letter]. Arch Ophthalmol. 1976;94:168.
10. Kaback MB, Podos SM, Harbin TS Jr, et al. The effects of dipivalyl epinephrine on the eye. Am J Ophthalmol.
1976;81:768-772.
11. Woodward DF, Novack GD, Williams LS, et al. Dihydrolevobunolol is a potent ocular beta-adrenoceptor
antagonist. J Ocul Pharmacol. 1987;3:11-15.
12. Bito LZ, Stjernschantz J, Resul B, et al. The ocular effects of prostaglandins and the therapeutic potential of a
new PGF2 alpha analog, PhXA41 (latanoprost), for glaucoma management. J Lipid Mediat. 1993;6:535-543.
13. Quigley HA, Pollack IP. Intraocular pressure control with twice-daily pilocarpine in two vehicle solutions. Ann
Ophthalmol. 1977;9:427-430.
14. Laurence J, Holder D, Vogel R, et al. A double-masked, placebo-controlled evaluation of timolol in gel vehicle. J
Glaucoma. 1993;2:177-182.
15. Diestelhorst M, Fauser S, Gruner K, Sueverkruep R. The ocular bioavailability of latanoprost lyophilizate 0.75 mg
compared with Xalatan(R) 1.5 mg [ARVO abstract 5307]. Invest Ophthalmol Vis Sci. 2010;51(5).
16. Novack GD, Ober M, Batoosingh AL, et al. Low dose clonidine on an ophthalmic rod is effective in reducing
elevated intraocular pressure. Invest Ophthalmol Vis Sci. 1988;29 (3)(suppl):83.
17. Gwon A, Borrmann LR, Duzman E, et al. Ophthalmic rods: new ocular drug delivery devices. Ophthalmology.
1986;93(S):82-85.
18. Kaufman HE, Uotila MH, Gasset AR, et al. The medical uses of soft contact lenses. Trans Am Acad Ophthalmol
Otolaryngol. 1971;75:361-373.
19. Daull P, Buggage R, Lambert G, et al. A comparative study of a preservative-free latanoprost cationic emulsion
(Catioprost) and a BAK-preserved latanoprost solution in animal models. J Ocul Pharmacol Ther. 2012;28(5):515523.
20. Robin AL, Suan EP, Sjaarda RN, et al. Reduction of intraocular pressure with anecortave acetate in eyes with
ocular steroid injection-related glaucoma. Arch Ophthalmol. 2009;127:173-178.
21. Wong TT, Novack GD, Ho CI, et al. Nanomedicine for glaucoma: a new therapeutic option with substantial
benefits over conventional eyedrops. Drug Deliv Transl Res. In press.
22. Alm A, Widengard I, Kjellgren D, et al. Latanoprost administered once daily caused a maintained reduction of
intraocular pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol. 1995;79:12-16.
23. Driot JY, Novack GD, Rittenhouse KD, et al. Ocular pharmacokinetics of fluocinolone acetonide after Retisert
intravitreal implantation in rabbits over a 1-year period. J Ocul Pharmacol Ther. 2004;20:269-275.